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BTB domain-containing 7 predicts low recurrence and suppresses tumor progression by deactivating Notch1 signaling in breast cancer

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Abstract

Purpose

BTB domain-containing 7 (BTBD7) has been found to regulate epithelial tissue remodeling and branched organ formation and has been reported to modulate the biological behavior of several cancers. However, its role in breast cancer has not been identified. This study investigated the biological role and prognostic value of BTBD7 in breast cancer.

Methods

We identified the BTBD7 expression pattern using the GENT2 database and assessed its expression in breast cancer tissue and cell lines using quantitative reverse transcription polymerase chain reaction, western blot, and immunohistochemistry. We conducted a clinical relevance and survival analysis on a cohort of 121 breast cancer cases from our follow-up and validated it in a Kaplan–Meier plotter. The gain–loss effect of BTBD7 on cell proliferation, invasion, and migration was detected in vitro. We employed a xenograft mouse metastatic model for in vivo validation and performed a Cignal Finder Cancer 10-Pathway Reporter Array, western blot, immunofluorescence, Cell Counting Kit-8, and transwell invasion/migration assays to analyze the potential mechanism.

Results

BTBD7 was downregulated in human breast cancer cell lines and tissues. Decreased BTBD7 expression correlated with a positive lymph node status, lymphovascular invasion, and TNM stage, while high BTBD7 expression correlated with low breast cancer recurrence. BTBD7 suppressed cell proliferation, invasion/migration, and tumor metastasis in breast cancer. The mechanism studied suggested that the inhibitory role of BTBD7 was through the deactivation of Notch1 signaling in breast cancer.

Conclusion

BTBD7 suppresses tumor progression, and its high expression correlates with low recurrence in breast cancer.

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Data availability

The datasets used during the current study are available from the corresponding author upon reasonable request.

Abbreviations

BTBD7:

BTB domain-containing 7

BC:

Breast cancer

PBC:

Peri-tumor tissue of breast cancer

IDC:

Invasive ductal carcinoma

IHC:

Immunohistochemistry

qRT-PCR:

Quantitative Real-time PCR

ISH:

In situ hybridization

IRS:

Immunoreactive score

ER:

Estrogen receptor

PR:

Progesterone receptor

Her2:

Human Epidermal Growth Factor Receptor type 2

TNM:

Tumor node metastasis

OS:

Overall Survival

RFS:

Recurrence-Free Survival

GENT:

Gene Expression database of Normal and Tumor tissues

FC:

Fold change

DMSO:

Dimethylsulfoxide

N1ICD:

Notch1 intracellular domain

FUP1:

Function-unknown protein 1

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Acknowledgements

We thank Prof. Zun-fu Ke (Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University) and his colleagues for the help of pathological diagnoses and guidance.

Funding

This study was funded by National Natural Science Foundation of China (No. 81802599).

Author information

Authors and Affiliations

  1. Department of Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 510080, Guangzhou, Guangdong, China

    Jian Chen

  2. Department of Thyroid and Breast Surgery, The Eastern Division of the First Affiliated Hospital of Sun Yat-Sen University, 510700, Guangzhou, Guangdong, China

    Jian Chen & Yuan-Hui Lai

  3. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Road II, 510080, Guangzhou, Guangdong, China

    Shiyin Ooi & Tian-Yu Liu

  4. Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, 510080, Guangzhou, Guangdong, China

    Yan Song

  5. Center for Proteomics and Metabolomics, State Key Laboratory of Bio-Control,, Guangdong Province Key Laboratory for Pharmaceutical Functional GenesSchool of Life Sciences, Sun Yat-Sen University, 510006, Guangzhou, Guangdong, China

    Lu Li

Authors
  1. Jian Chen
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  2. Yuan-Hui Lai
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  4. Yan Song
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  5. Lu Li
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Corresponding author

Correspondence to Tian-Yu Liu.

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Conflict of interest

All authors declare no conflict of interest.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All of the animal experiments were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All human-related procedures were performed with the approval of the Internal Review and the Ethics Boards of the First Affiliated Hospital, Sun Yat-sen University.

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Informed consent was obtained from all individual participants included in the study.

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Chen, J., Lai, YH., Ooi, S. et al. BTB domain-containing 7 predicts low recurrence and suppresses tumor progression by deactivating Notch1 signaling in breast cancer. Breast Cancer Res Treat 184, 287–300 (2020). https://doi.org/10.1007/s10549-020-05857-2

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  • DOI: https://doi.org/10.1007/s10549-020-05857-2

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